key: cord-0695095-35lrqh5w authors: Babaei, Amirhossein; Iravani, Kamyar; Malekpour, Behzad; Golkhar, Behnaz; Soltaniesmaeili, Amir; Hosseinialhashemi, Milad title: Factors associated with anosmia recovery rate in COVID‐19 patients date: 2021-11-02 journal: Laryngoscope Investig Otolaryngol DOI: 10.1002/lio2.690 sha: c4b9186dbcfba3ee5c537975ef565650d49847d7 doc_id: 695095 cord_uid: 35lrqh5w OBJECTIVES: The present study aimed to assess the 4‐ and 8‐week recovery rate of anosmia and determine the factors associated with recovery in COVID‐19 patients. METHOD: This retrospective study was conducted from December 2020 to March 2021. RT‐PCR‐proven COVID‐19 adult patients (over 18 years of age) with a positive history of anosmia were included in this study. Anosmia was assessed based on the COVID‐19 Anosmia Reporting Tool. The recovery rate of anosmia after 4 and 8 weeks were evaluated, and the relationship between the patients' recovery and their clinical and demographic data was assessed. RESULTS: A total of 235 patients were included. Their mean age (±SD) was 43.95 ± 15.27 years. Anosmia recovery was reported in 207(88.51%) and 219 (93.19%) participants till 4 and 8 weeks. The mean recovery time was 19.42 ± 8.81 days. The result of logistic regression showed that smoking (P = .031; OR = 10.813), ageusia (P = .002; OR = 5.340), headache (P = .006; OR = 0.243), and nasal discharge (P < .001; OR = 0.080) were significantly associated with 4 weeks anosmia recovery. The only risk factor which was associated with a lower rate of 8 weeks anosmia recovery was presence of nasal discharge (OR = 0.106, P = .002). CONCLUSION: The only risk factor which was associated with a lower rate of 8 weeks anosmia recovery was presence of nasal discharge. Our result demonstrated that although smoking was associated with higher recovery rate till 4 weeks, it could not be considered as a protective factor after 8 weeks. More studies are recommended to investigate the relationship between anosmia and the associated factors by consideration of both short‐ and long‐term recovery rates and assess the possible mechanisms that could justify this association. LEVELS OF EVIDENCE: 3b Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The common symptoms of COVID-19 include dry cough, fever, dyspnea, fatigue, anorexia, diarrhea, chest pain, headache, and muscle ache. 1, 2 Anosmia and dysgeusia are two complaints that were reported among individuals with positive PCR tests of SARS-CoV-2 infection. 3 This has led to an increased diagnosis of olfactory and gustatory dysfunction, which has overlapped with the COVID-19 pandemic. The Center for Disease Control (CDC) accepted anosmia and dysgeusia as major signs of COVID-19 infection. 4 A recent meta-analysis including 32 142 COVID-19 patients from 107 studies reported anosmia in 12 038 patients with a prevalence of 38.2% (95% CI: 36.5%, 47.2%). 5 Other studies have reported that anosmia is resolved in most patients within 2 to 3 weeks. 6, 7 Currently, there is no definite treatment for post-COVID anosmia. Olfaction is an important sense in human life, and for responses to the environment, determining the recovery time of olfactory damage and its related factors is important in patients with anosmia. Lucidi et al investigated olfactory recovery after COVID-19 infection using the patient-reported "American Academy of otolaryngology-head and neck surgery COVID-19 anosmia reporting tool for clinicians" to evaluate the status of anosmia. They reported that the only factor that was adversely related to anosmia recovery was cigarette smoking. 8 In the present study, 4 and 8 weeks periods were considered to determine the factors associated with recovery from anosmia among COVID-19 patients. Positive history of cigarette smoking was defined as "at least one cigarette per day" and positive alcohol use was defined as "at least one drink per week." Positive history of allergy was obtained by asking patients about symptoms of allergic rhinitis (seasonal, occupational, etc.). All data were gathered through interviews. Anosmia was assessed based on the COVID-19 Anosmia Reporting Tool, developed by the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS). 9 The demographic and clinical data of the two groups were compared. The recovery rate of anosmia after 4 and 8 weeks (30 and 60 days) was evaluated as the main outcome, and the relationship between the patients' recovery and their clinical and demographic data was assessed. Moreover, the status of anosmia was compared between these two periods. Categorical variables were reported as frequency and percentage, and quantitative variables were expressed as mean (±SD). Chi-square or Fisher's exact tests were used to evaluate possible associations among the categorical variables, if appropriate. Parametric and nonparametric continuous variables were analyzed using paired sample ttest, independent t-test, Mann-Whitney U tests, and Wilcoxon, where applicable. Then, all associations with a P < .2 were included in the logistic regression. A P < .05 was considered statistically significant. Analyses were conducted using SPSS 25 software (SPSS Inc., Chicago, Illinois). In total, 235 patients with a mean age (±SD) of 43.95 ± 15.27 years were included in this study. Complete self-reported anosmia recovery was stated in 207 participants (88.51%) at 4 weeks. After 8 weeks, recovery was reported in 12 patients (5.10%) with a mean of 40.50 days and the overall recovery rate was 93.19% (219 patients) after 8 weeks. The mean recovery time was 19.42 ± 8.81 days. Quantitative demographic and clinical data of the patients are presented in Table 1 . In 23 patients (9.8%), anosmia was the first symptom of COVID-19 infection. Univariate analysis showed smoking, ageusia, headache, and nasal discharge were significantly correlated with recovery after 4 weeks (P = .008, P = .006, P = .013, and P < .001, respectively) ( Figure 1 ). Detailed qualitative demographic and clinical data of the patients after 4 weeks are reported in Table 2 . Univariate analysis showed smoking, allergy, headache, and nasal discharge were significantly correlated with recovery after 8 weeks (P = .026, P = .006, P = .020, and P = .001, respectively) ( Figure 2 ). Detailed qualitative demographic and clinical data of the patients after 8 weeks are reported in Table 3 . The result of logistic regression showed that smoking, ageusia, headache, and nasal discharge were significantly associated with anosmia recovery (P = .031, P = .002, P = .006, and The result of logistic regression showed that nasal discharge was significantly associated with a lower rate of recovery (OR = 0.106, P = .002) after 8 weeks. Table 4 shows the results of the logistic regression test. Based on the rate of cigarette smoking after 4 weeks and considering α = 0.05 and β = 0.2, the study power was calculated at 91.2%. This study assessed the association between anosmia and the demographic and clinical characteristics of patients with COVID-19. The results showed that a history of smoking and the presence of ageusia in patients were associated with a higher rate and the presence of headache and nasal discharge was associated with a lower rate of 4-week recovery. The only risk factor which was associated with a lower rate of 8 weeks anosmia recovery was presence of nasal discharge. Altered smell and taste sensations are important complaints during the pandemic of COVID-19. Anosmia can occur with or without ageusia, and it is a prevalent symptom among patients with COVID-19 with a range of 19.4% to 88%. 10 gustatory dysfunction was the initial symptom in 14.9% of patients. 16 Another study reported anosmia as the first symptom in 24% of patients. 11 In the present study, the mean age of participants was near 44 years. The mean age was lower in the group without recovery than in the groups with anosmia recovery, but the difference was not statistically significant. One research concluded that the risk of olfactory dysfunction was higher in younger patients than older ones. 17 Such a result was reported by Giacomelli et al, who stated that anosmia was more common in younger patients (median age, 56 vs 66 years). 18 The reason may be more comorbidities in older patients, and olfactory dysfunction may not be recognized; consequently, this issue has not been commonly described. 17 Numerous studies have shown that the median age for anosmia is about 50 years. 11, 17 Most of the patients in the current study were male, in line with some other studies. However, the majority of studies have reported that females are more susceptible to COVID-19-related anosmia. [19] [20] [21] Interestingly, the current study revealed that cigarette smoking was associated with an increased rate of anosmia recovery rate by 4 weeks but not after 8 weeks. Several previous studies have mentioned that anosmia is more prevalent among smokers, and the recovery rate of anosmia is reduced in smoker patients. 4, 17, 22, 23 An experimental study by Vent et al on rats concluded that the rate of anosmia was higher in smokers than nonsmokers because of increased death in olfactory sensory neurons by cigarette smoking. 24 showed that smoking was significantly associated with a higher rate of recovery of anosmia after 6 months (P = .044; odds ratio: 25.96). 8 Our result demonstrated that although smoking was associated with higher recovery rate till 4 weeks, but it could not be considered as a protective factor after 8 weeks. infection among smoker individuals. They justify this observation with two hypotheses. The first hypothesis considers a global effect on the renin-angiotensin system, of which ACE2 is only a part, by up-regulating the ACE1 receptor and down-regulating the ACE2 receptor. The second theory emphasizes the interaction between ACE2 and the nicotinic receptors (especially α7 nicotine receptors). This receptor is near the ACE2 receptors on the cell membrane. The dysregulation of these receptors might trigger a Th1 immune response. Nicotine and SARS-Cov2 might as well compete for binding to nicotinic acetylcholine receptors (nAchRs). 27 These mechanisms could be considered to justify the higher 4 weeks recovery rate of olfactory dysfunction in the current study and other recent studies. Smell and taste sensations are closely related to each other. Anosmia may cause dysgeusia or ageusia. 28 The recommended pathophysiology for dysgeusia in COVID-19 is cranial nerve dysfunction (particularly the seventh cranial nerve), zinc deficiency, interaction with sialic acid receptors, direct virus attack to the buccal and gingival tissues, taste buds in the tongue, and salivary glands. 5 In the current study, 62.1% of the patients reported ageusia. Similarly, in a study by Thakur et al, 77.7% of anosmic patients complained of gustatory dysfunction. 11 The current results showed that the presence of ageusia was associated with a higher rate of 4 weeks anosmia recovery but not 8 weeks anosmia recovery. This was in line with the results of Rashid, who reported that the co-presentation of anosmia and ageusia had a positive significant effect on the recovery time of anosmia in patients using nasal betamethasone drops. 23 In the current study, the presence of headache was linked with a lower 4 weeks recovery rate. The association between headache and anosmia has been reported in previous investigations as well. 29 Headache is generally diffuse, very severe, and with a migraine phenotype. 30 In the present study, nasal discharge was associated with a lower rate of anosmia recovery both till 4-and 8-week periods. Although it could be justified with conductive anosmia, some studies have mentioned that it was not correlated with olfactory dysfunction. 15, 31 One of the strengths of the present study was its use of a uniform Although this study included a large sample size in comparison with other similar studies, which is an important strength, the association between smoking and the higher rate of anosmia recovery till 4 weeks is related to the small number of patients in the no-recovery F I G U R E 2 Eight weeks recovery rate in patients with (+) and without (À) nasal discharge, headache, ageusia, and smoking group and, by chance, the small number of smokers (N = 1) in that group. Therefore, it may be susceptible to spectrum bias related to the patient population and, hence, possibly not a real association. As mentioned above, our result demonstrated that although smoking was associated with higher recovery rate till 4 weeks, but it could not be considered as a protective factor after 8 weeks. The current study has some limitations. The first one was the retrospective nature of the study. The second limitation was that packyears of smoking and its relation to the recovery rate of anosmia were not evaluated. Due to the substantial risk of contamination in the acute phase of infection and initial stage of anosmia, no objective olfactory tests were conducted, and data were gathered using the COVID-19 Anosmia Reporting Tool. This limitation is common in most investigations on anosmia in COVID-19 patients. The only risk factor which was associated with a lower rate of 8 weeks anosmia recovery was presence of nasal discharge. 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Persistent headache and persistent anosmia associated with COVID-19 Headache associated with COVID-19: frequency, characteristics and association with anosmia and ageusia New loss of smell and taste: uncommon symptoms in COVID-19 patients on Factors associated with anosmia recovery rate in COVID-19 patients The authors declare that they have no conflict of interest. https://orcid.org/0000-0003-0251-1712Kamyar Iravani https://orcid.org/0000-0001-8302-2683